Heterocyclic glucocorticoid receptor modulators with a 2,2-dimethyl-3- phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core

Article abstract of DOI:10.1016/j.bmcl.2013.08.049

A series of heterocyclic glucocorticoid receptor (GR) modulators with 2,2-dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core are described. Structure-activity relationships suggest a combination of H-bond acceptor and a 4-fluorophenyl moiety as being important structural components contributing to the glucocorticoid receptor binding and functional activity for this series of GR modulators.

Full text of DOI:10.1016/j.bmcl.2013.08.049

Accepted Manuscript
Heterocyclic glucocorticoid receptor modulators with a 2,2-dimethyl-3-phenyl-
N-(thiazol or thiadiazol-2-yl)propanamide core
Hai-Yun Xiao, Dauh-Rurng Wu, James E. Sheppeck II, Sium F. Habte, Mark
D. Cunningham, John E. Somerville, Joel C. Barrish, Steven G. Nadler, T.G.
Murali Dhar
PII:
S0960-894X(13)00989-X
http://dx.doi.org/10.1016/j.bmcl.2013.08.049
BMCL 20787
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Accepted Date:
1 July 2013
9 August 2013
Please cite this article as: Xiao, H-Y., Wu, D-R., Sheppeck, J.E. II, Habte, S.F., Cunningham, M.D., Somerville,
J.E., Barrish, J.C., Nadler, S.G., Murali Dhar, T.G., Heterocyclic glucocorticoid receptor modulators with a 2,2-
dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core, Bioorganic & Medicinal Chemistry Letters
(2013), doi: http://dx.doi.org/10.1016/j.bmcl.2013.08.049
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Heterocyclic glucocorticoid receptor
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modulators with a 2,2-dimethyl-3-phenyl-N-
(thiazol or thiadiazol-2-yl)propanamide core
Hai-Yun Xiao, Dauh-Rurng Wu, James E. Sheppeck II, Sium F. Habte, Mark D. Cunningham, John E.
Somerville, Joel C. Barrish, Steven G. Nadler and T. G. Murali Dhar*

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Heterocyclic glucocorticoid receptor modulators with a 2,2-dimethyl-3-phenyl-N-
(thiazol or thiadiazol-2-yl)propanamide core
Hai-Yun Xiao, Dauh-Rurng Wu, James E. Sheppeck II, Sium F. Habte, Mark D. Cunningham, John E.
Somerville, Joel C. Barrish, Steven G. Nadler and T. G. Murali Dhar*
a
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ-08543-4000
* Corresponding author. Tel.: 609-252-4158; fax: 609-252-7410; e-mail: murali.dhar@bms.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of heterocyclic glucocorticoid receptor (GR) modulators with 2,2-dimethyl-3-phenyl-N-
(thiazol or thiadiazol-2-yl)propanamide core are described. Structure-activity relationships
suggest a combination of H-bond acceptor and a 4-fluorophenyl moiety as being important
structural components contributing to the glucocorticoid receptor binding and functional activity
for this series of GR modulators.
2013 Elsevier Ltd. All rights reserved.
Keywords:
Glucocorticoid receptor
Non-steroidal glucocorticoid receptor agonists
Dissociated steroids
Transrepression
Transactivation
The glucocorticoid receptor (GR) is a member of the steroid
family of nuclear hormone receptors that is involved in
modulating a variety of immunological and metabolic signaling
synthesis heterocyclic GR modulators (3) employing novel
approaches and the SAR, which is rationalized based on the X-
ray
co-crystal
structure
of
a
pyrazole
based
pathways upon glucocorticoid binding.
immunosuppressive and anti-inflammatory
The effective
effects of
diphenylpropionamide GR agonist and deacylcortivazol, with the
glucocorticoid receptor ligand binding domain (GR-LBD).
glucocorticoids like prednisone is unfortunately often
accompanied by significant adverse effects like osteoporosis,
metabolic and cardiovascular disease on long term usage. Given
the recent advances in understanding the mechanisms of
glucocorticoid receptor action, there has been a significant effort
in academia and industry to selectively target the beneficial anti-
inflammatory effects (transrepression) over the adverse effects
attributed to transactivation of certain genes using “dissociated”
steroids and non-steroidal glucocorticoid receptor agonists.1
Representative synthetic pathways utilized in the preparation
of these heterocycles is outlined in Schemes 1-3. The key step in
these reactions is a variation of the Mukaiyama aldol reaction i.e.
the addition of silylketene acetal of methyl isobutyrate under
Lewis acid conditions to a highly electrophilic bisbenzylic
alcohol.
Figure 1. Heterocycle based GR modulators
We
recently
reported
on
a
series
of
hexahydroimidazo[1,5b]isoquinoline (HHII) (1)2a derived GR
modulators and pyrazolodiphenylpropionamide-based GR
agonists (2)2b where the basic imidazole ring of the HHII scaffold
and the pyrazole ring of 2 served as replacements for the A-B
ring of the steroid scaffold (Figure 1). This report describes the
Scheme 1. Reagents and conditions: (a) Me2NCOCl, NaH, DMF,
97%; (b) PhMgBr, THF, 100%; (c) CH2Cl2, BF3.OEt2, 97%, (d)
NaOH, MeOH, DMSO, 91%; (e) 1-bromo-4-fluorobenzene, CuI,
trans-cyclohexane-1,2-diamine, K2CO3, Bu4NI, dioxane, 56%; (f) 2-
aminothiazole, HATU, EtNPri2, DMF, 22-75%.

We previously reported on in vitro assays to characterize GR
binding, transrepression (AP-1) and transactivation (Gal4-
reporter).1l Table 1 outlines GR binding data for the six
heterocycles examined.
quinoline does not allow it to effectively engage in a H-bonding
interaction with Arg611. The GR binding potency of indole (6)
is probably due to the interaction of the indole NH with Gln570
on helix 3 of the GR LBD. Although 4, 6, 8 and 9 were potent in
the GR binding assay, significant improvements in functional
potency (as evidenced by the lack of significant activity in the
AP-1 assay) was needed for the compounds to be evaluated
further.
Table 1. SAR around the heterocyclic corea
Compd
No.
GR
AP-1 repression
Ki, (nM) EC50, (nM) (eff % dex)b
Dexamethasone 1.1
2.5
(100)
(61)
4
5
6
7
8
9
15
85
7
169
13
18
>10000
>10000
230
>10000
>10000
1200
Scheme 2. Reagents and conditions: (a) DMF, K2CO3, 85oC, 16
h, 29%; (b) NaOH, EtOH, 92%; (c) MeO(Me)NH-HCl, EDCI,
EtNPri2, HOBt, MeCN, 100%; (d) PhMgBr, THF, 77%; (e) NaBH4,
THF, EtOH, 100%; (f) Me2C=C(OMe)OSiMe3, BF3.OEt2, CH2Cl2,
78%; (g) LiOH, H2O, dioxane, 95%; (h) chiral separation using
CHIRALPAKAD-H column; (i) 2-aminothiazole, HATU, EtNPri2,
DMF, 90-94%
(39)
a Values are means of at least two experiments done in triplicate. b
Efficacy represented as a percentage of the maximal response of
dexamethasone (100%). %dex is not reported where <5%.
As was originally described by Hirshman et. al,3
incorporation of a 4-fluorophenyl moiety at the N-1 position of a
pyrazole- (which serves as an A-ring mimic of steroids),
significantly improves the functional potency relative to the des-
fluorophenyl analog. In the reported X-ray co-crystal structure of
deacylcortivazol with GR LBD,4 key interactions include the
engagement of pyrazole N-2 with Gln570 and the significant
expansion of the GR binding pocket to accommodate the
arylpyrazole moiety.
As is evident from the table isoquinoline (4), and the two
isomeric imidazopyridines (8, 9) are potent binders of GR. The
potency of quinoline (5) in the GR binding assay is significantly
lower compared to the isoquinoline (4). This was not completely
unexpected since the X-ray co-crystal structure of a pyrazole
based diphenylpropionamide GR agonist with the ligand binding
domain (LBD) of GR2b clearly indicates an important H-bonding
interaction of the nitrogen atom with Arg611 residue on helix 5.
It is possible that the trajectory of the nitrogen atom in case of the
Table 2. Phenyl substituted heterocyclesa
Compd
No.
GR
Ki, (nM)
AP-1 repression
EC50, (nM) (eff % dex)b
GAL 4 reporter
EC50 (nM) (eff % dex)b
Dexamethasone
10
11
12
1.1
285
196
13
3
2.5
(100)
4.2
(100)
>10000
>10000
220
(60)
(66)
13
16
103
(74)
13 enantiomer1
13 enantiomer2
14
14 enantiomer1
14 enantiomer2
15
4
1
3
6
2
5
>5000
6
36
1200
24
60
>10000
60
262
>10000
118
360
(73)
(68)
(24
(72)
(70)
(69)
(66)
(65)
(32)
15 enantiomer1
15 enantiomer2
16
16 enantiomer1
16 enantiomer2
11
2
3
5
1
>2500
23
899
1122
254
>10000
147
2000
>10000
613
(67)
(66)
(34)
(61)
(51)
(30)
(43)
a Values are means of at least two experiments done in triplicate. b Efficacy represented as a percentage of the maximal response of
dexamethasone (100%). %dex is not reported where <5%.

This observation has been taken advantage of by a number of
groups who have incorporated 4-fluorophenyl moiety into non-
steroidal GR modulators leading to compounds with dissociated
profiles. By analogy to what has been described above, we
reasoned that incorporating the 4-fluorophenyl moiety to
scaffolds 4, 6, 8 and 9 should lead to compounds with improved
functional potency.
lack of a H-bond donor in compound 12 is compensated by the
gain in hydrophobic interactions of the 4-fluorophenyl moiety
with the “arylpyrazole” pocket of GR. However, the loss of both
binding potency for the 4-fluorophenylisoquinoline analog was
surprising (compare 10 with 4). In contrast, however, the
imidazopyridines (13 and 15) showed significant improvements
in functional potency when compared to their des-phenyl or des-
fluorophenyl analogs, 8 and 9 respectively, suggesting that the 4-
fluorophenyl moiety in the isoquinoline analog 10, may not have
the right trajectory to be accommodated in the “arylpyrazole”
pocket of GR.
The synthesis of compound 15 is outlined in Scheme 2 and the
GR binding and functional data for the corresponding compounds
is shown in Table 2.
As is clear from Table 2, appending the 4-fluorophenyl moiety
to the indole did not lead to significant changes in functional
potency, as judged by the activity of the compound in the AP-1
assay (compare compound 12 with 6). This may be because the
The enantiomers of compound 15 were prepared from the
corresponding acid intermediate (step h, Scheme 2) and their
potency in the GR binding and functional assays was established.
As Table 2 indicates, both compounds displayed similar potency
Scheme 3. Reagents and conditions: (a) PhMgBr, THF, 100%; (b) Ac2O, DMAP, EtNPri2, CH2Cl2, 92%; (c) Me2C=C(OMe)OSiMe3, TiCl4,
CH2Cl2, 79%; (d) Zn(CN)2, PdCl2-dppf-CH2Cl2, Zn, DMA, 120oC, 2h, 63%; (e) H2, Pd/C, HCl, MeOH, 2.5h, 98%; (f) HCO2H, 90oC, 73%; (g)
POCl3, PhMe, 115oC, 94%; (h) NBS, MeCN, -10oC then RT, 56%; (i) chiral separation using CHIRALPAKAD-H column; (j) LiOH, H2O,
dioxane 100%; (k) ArB(OH)2, PdCl2-dppf-CH2Cl2, K3PO4, DMF, 90oC; (l) 2-aminothiazole or 2-amino-1,3,4-thiadiazole, HATU, EtNPri2,
DMF, 30-60% combined yield for (k) and (l).
Table 3. Substituted 1-phenylimidazo[1,5-a]pyridine enantiomer 2 analogsa
Compd
No.
Structure
R1
GR
R3
AP-1 repression
GAL 4 reporter
X
R2
Ki, (nM) EC50, (nM) (eff % dex)b
EC50 (nM) (eff % dex)b
Dexamethasone
1.1
4
4
4
2
5
2
1
8
2.5
(100)
(30)
(32)
(37)
(37)
4.2
(100)
18
19
20
21
22
23
24
25
26
CH
N
CH
N
N
CH
N
CH
N
H
H
H
H
H
F
F
H
H
CN
CN
H
H
H
CN
CN
H
F
F
F
F
225
1350
89
140
>5000
14
15
114
111
>10000
>10000
>10000
>10000
>10000
78
117
>10000
>10000
H
CH2OH
H
H
Cl
Cl
(75)
(69)
(26)
(20)
(73)
(61)
5
a Values are means of at least two experiments done in triplicate. b Efficacy represented as a percentage of the maximal response of
dexamethasone (100%). %dex is not reported where <5%.

Sasse, R. Z.; Taylor, S. J.; Uings, I. J.; Trump, R. P. J. Med.
Chem. 2010, 53, 4531– 4544; (h) Shah, N.; Scanlan, T. S. Bioorg.
Med. Chem. Lett. 2004, 14, 5199–5203; (i) De Bosscher, K.;
Vanden Berghe, W.; Beck, I. M.; Van Molle, W.; Hennuyer, N.;
Hapgood, J.; Libert, C.; Staels, B.; Louw, A.; Haegeman, G.
Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 15827–15832; (j)
Robinson, R. P.; Buckbinder, L.; Haugeto, A. I.; McNiff, P. A.;
Millham, M. L.; Reese, M. R.; Schaefer, J. F.; Abramov, Y. A.;
Bordner, J.; Chantigny, Y. A.; Kleinman, E. F.; Laird, E. R.;
Morgan, B. P.; Murray, J.C.; Salter, E.D.; Wessel,M.D.; Yocum,
S. A. J. Med. Chem. 2009, 52, 1731–1743; (k) Riether, D.;
Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J.;
Pack, E. J., Jr.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T.
N.; Zuvela-Jelaska, L.; Pelletier, J.; Dinallo, R.; Panzenbeck, M.;
Torcellini, C.; Nabozny, G. H.; Thomson, D. S. J. Med. Chem.
2010, 53, 6681–6698; (l) Yang, B. V.; Weinstein, D. S.;
Doweyko, L. M.; Gong, H.; Vaccaro, W.; Huynh, T.; Xiao, H.;
Doweyko, A. M.; McKay, L.; Holloway, D. A.; Somerville, J. E.;
Habte, S.; Cunningham, M.; McMahon, M.; Townsend, R.;
Shuster, D.; Dodd, J. H.; Nadler, S. G.;Barrish, J. C. J. Med.
Chem. 2010, 53, 8241–8251; (m) Weinstein, D. S.; Gong, H.;
Doweyko, A. M.; Cunningham, M.; Habte, S.; Wang, J.;
Holloway, D. A.; Burke, C.; Gao, L.; Guarino, V.; Carman, J.;
Somerville, J. E.; Shuster, D.; Salter-Cid, L.; Dodd, J. H.; Nadler,
S. G.; Barrish, J. C. J. Med. Chem. 2011, 54, 7318–7333; (n)
Bungard, C. J.; Hartman, G. D.; Manikowski, J. J.; Perkins, J. J.;
Chang, B.; Brandish, P. E.; Euler, D. H.; Hershey, J. C.;
Schmidt, A.; Fang, Y.; Norcross, R. T.; Rushmore, T. H.;
Thompson, C. D.; Meissner, R. S. Bioorg. Med. Chem. Lett.
2011, 19, 7373-7386.
in the GR binding assay, however, enantiomer 2 was
significantly more potent in the functional assay than enantiomer
1. A similar trend was noticed for the thiadiazole analogs (16
enantiomer 1 and 2) and the imidazopyridine isomers (13
enantiomer 1 and 2 and 14 enantiomer 1 and 2). The absolute
configuration of the more active isomer was not established.
Since the binding and functional potencies of the
imidazopyridines (13 and 15) were similar, we decided to use
imidazopyridine (13) to further investigate the 4-fluorophenyl
SAR because of the accessibility of the key bromo intermediate
(17, Scheme 3) for Suzuki coupling reactions. The Suzuki
coupling reactions were carried out using the homochiral bromo
compound (enantiomer 2, step i, Scheme 3) derived from
intermediate (17), since compounds derived from this
intermediate were active in the functional assay as shown in
Table 2. Reaction conditions for the Suzuki coupling reaction
are shown in Scheme 3 and the GR binding and functional data
for the corresponding analogs is shown in Table 3. 5
In general most compounds were potent in the GR binding
assay.
However, for the limited number of compounds
examined, the fluoro (13, 14, Table 2) and the difluoroanalogs
(23, 24, Table 3) had the best functional potency in the AP-1
assay. A significant loss in functional potency (AP-1) was seen
with meta substituted (18, 19, 22) or meta-para disubstituted
analogs (25, 26). A small group at the para position appears to
be preferred since there is a significant loss in functional potency
in the AP-1 assay with the p-cyano analog (20, 21).
2. (a) Xiao, H.-Y.; Wu, D.-R.; Malley, M. F.; Gougoutas, J. Z.;
Habte, S. F.; Cunningham,M. D.; Somerville, J. E.; Dodd, J. H.;
Barrish, J. C.; Nadler, S. G.; Dhar, T. G. M. . J.Med. Chem. 2010,
53, 1270–1280; (b) Sheppeck, J. E.; Gilmore, J. L.; Xiao, H-X.;
Dhar, T. G. M.; Nirschl, D.; Doweyko, Sack, J. S.; A. M.; Corbett,
Malley, M. F.; Gougoutas, J. Z.; McKay, L.; Cunningham, M. D.;
Habte, S. F.; Dodd, J. H.; Nadler, S. G.; Somerville, J. E.; Barrish,
J. C. Bioorg. Med. Chem. Lett. (in press).
3. Hirschmann, R.; Steinberg, N. G.; Buchschacher, P.; Fried, J. H.;
Kent, G. J.; Tishler. J. Am. Chem. Soc. 1963, 85, 120-122.
4. Suino-Powell, K.; Xu, Y.; Zhang, C.; Tao, Y.-G.; Tolbert, W.
D.;Simons, S. S.; Xu, H. E. Mol. Cell. Biol. 2008,
28, 1915–1923.
5. Dhar, T. G. M.; Xiao, H-X.; Sheppeck, J. E. U. S. Patent 7 994
In conclusion, a series of novel heterocyclic modulators of
glucocorticoid receptor have been identified. SAR suggests that
a combination of a H-bond acceptor (probably engaging Gln570
or Arg611) and a 4-fluoropheny substituent is optimal for
improving functional potency in the AP-1 transrepression assay.
Unfortunately, compounds that were active in the transrepression
assay were also potent in the in vitro functional transactivation
assay (GAL4 assay) and therefore were not pursued further as
non-steroidal GR agonists.
190, 2011.
Acknowledgments
We are grateful to the following colleagues for their support of
the project and their help in the preparation of this manuscript:
Mary Ellen Cvijic, Ding Ren Shen and Melissa Yarde.
References and notes
1. (a) Berlin, M. Expert Opin. Ther. Pat. 2010,
20, 855–873; (b) Regan, J.; Razavi, H.; Thomson, D. Annual
Reports in Medicinal Chemistry; Elsevier: New York, 2008; Vol.
43, Chapter 9, pp 141-154; (c) Coghlan,M.J.; Kym, P. R.;
Elmore, S. W.; Wang, A. X.; Luly, J. R.; Wilcox, D.; Stashko, M.;
Lin, C.-W.; Miner, J.; Tyree, C.; Nakane, M.; Jacobson, P.; Lane,
B. C. J. Med. Chem. 2001, 44, 2879–2885; (d) Docke, W.-D.;
Strehlke, P.; Jaroch, S.; Schmees, N.; Rehwinkel, H.; Hennekes,
H.; Asadullah, K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 227–
232; (e) Ali, A.; Thompson, C. F.; Balkovec, J. M.; Graham, D.
W.; Hammond, M. L.; Quraishi, N.; Tata, J. R.; Einstein, M.; Ge,
L.; A.; Wang, C.; Williamson, J.; Miller, D. K.; Thompson,
C. M.; Zaller, D. M.; Forrest, M. J.; Carballo-Jane, E.; Luell, S. J.
Med. Chem. 2004, 47, 2441–2452; (f) Riether, D.; Harcken, C.;
Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J.; Pack, E. J.;
Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T. N.; Zuvela-
Jelaska, L.; Pelletier, J.; Dinallo, R.; Panzenbeck, M.; Torcellini,
C.; Nabozny, G. H.; Thomson, D. S. J. Med. Chem. 2010, 53,
6681–6698; (g) Yates, C. M.; Brown, P. J.; Stewart, E. L.; Patten,
C.; Austin, R. J. H.; Holt, J. A.; Maglich, J. M.; Angell, D. C.;